A Novel Homozygous Founder Variant of RTN4IP1 in Two Consanguineous Saudi Families

Mazhor Aldosary, Maysoon Alsagob, Hanan AlQudairy, Ana C. González-Álvarez, Stefan T. Arold, Mohammad Anas Dababo, Omar A. Alharbi, Rawan Almass, Al Bandary AlBakheet, Dalia AlSarar, Alya Qari, Mysoon M. Al-Ansari, Monika Oláhová, Saif A. Al-Shahrani, Moeenaldeen AlSayed, Dilek Colak, Robert W. Taylor, Mohammed AlOwain*, Namik Kaya*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1 Scopus citations


The genetic architecture of mitochondrial disease continues to expand and currently exceeds more than 350 disease-causing genes. Bi-allelic variants in RTN4IP1, also known as Optic Atrophy-10 (OPA10), lead to early-onset recessive optic neuropathy, atrophy, and encephalopathy in the afflicted patients. The gene is known to encode a mitochondrial ubiquinol oxidoreductase that interacts with reticulon 4 and is thought to be a mitochondrial antioxidant NADPH oxidoreductase. Here, we describe two unrelated consanguineous families from the northern region of Saudi Arabia harboring a missense variant (RTN4IP1:NM_032730.5; c.475G<T, p.Val159Phe) in the gene. Clinically affected individuals presented with intellectual disability, encephalopathy, ataxia, optic atrophy, and seizures. Based on whole exome sequencing and confirmatory Sanger sequencing, the variant was fully segregated with the phenotype in the families, absent among large ethnically matching controls as well as numerous in-house exomes, and predicted to be pathogenic by different in silico classifiers. Structural modeling and immunoblot analyses strongly indicated this variant to be pathogenic. Since the families belong to one of the tribal inhabitants of Saudi Arabia, we postulate that the variant is likely to be a founder. We provide the estimated age of the variant and present data confirming the disease-causality of this founder variant.

Original languageEnglish (US)
Article number3154
Issue number19
StatePublished - Oct 2022

Bibliographical note

Funding Information:
This research was funded by King Salman Center for Disability Research (KSCDR grant number #2180-004). The research from STA and ACC-A was supported by the King Abdullah University of Science and Technology (KAUST) through the baseline fund and the Award No. FCC/1/1976-25 and REI/1/4446-01 from the Office of Sponsored Research (OSR). R.W.T. is funded by the Welcome Centre for Mitochondrial Research (203105/Z/16/Z), the Mitochondrial Disease Patient Cohort (UK) (G0800674), the Medical Research Council International Centre for Genomic Medicine in Neuromuscular Disease (MR/S005021/1), the Medical Research Council (MR/W019027/1), the Lily Foundation, the UK NIHR Biomedical Research Centre for Ageing and Age-related disease award to the Newcastle upon Tyne Foundation Hospitals NHS Trust and the UK NHS Highly Specialised Service for Rare Mitochondrial Disorders of Adults and Children. MO and RWT are funded by the Pathological Society.

Publisher Copyright:
© 2022 by the authors.


  • age of variant
  • encephalopathy
  • founder variant
  • in silico pathogenicity prediction
  • missense
  • optic atrophy
  • RTN4IP1
  • structural modeling

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology


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